Human Immune Response to Haemophilus Ducreyi Infection

人类对杜克雷嗜血杆菌感染的免疫反应

• 批准号: 7336755
• 负责人: Stanley M. Spinola
• 金额: $ 36.98万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-01-01 至 2011-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7336755
• 关键词: Abscess; All Sites; Biology; Biopsy; Blood; CD 200; CD44 gene; CD58 gene; CD80 gene; CSF2 gene; Cell Communication; Cell Maturation; Cells; Clinical; Coculture Techniques; Dendritic Cells; Disease; End Point; Environment; Event; Failure; Gender; Gene Expression; Genital system; Germ; Goals; Granulocyte-Macrophage Colony-Stimulating Factor; Granuloma; HIV; HIV-1; Hemophilus ducreyi; Histopathology; Homologous Gene; Human; Human Genome; Human Volunteers; IRF1 gene; Immune; Immune response; Immunologics; In Vitro; Infection; Intercellular adhesion molecule 1; Interleukin-10; Interleukin-16; Interleukin-18; Interleukin-7; Lead; Lesion; Life; Modeling; Myelogenous; Organism; Outcome; Phagocytes; Phagocytosis; Phenotype; Physiologic pulse; Predisposition; Proliferating; Proteomics; Pulse taking; Puncture wound; Rate; Research Personnel; Serum; Simulate; Site; Skin; Staging; T-Lymphocyte; TLR1 gene; TNFRSF5 gene; Testing; Time; Tissue Microarray; Tissues; Transcript; Transudate; Ulcer; Upper arm; Week; Woman; acquired immunity; antigen processing; bactericide; comparison group; cytokine; day; falls; immune function; in vitro Model; in vivo; interleukin-23; killings; macrophage; men; neutrophil; notch protein; pathogen; programs; response; size; transmission process

Haemophilus ducreyi causes chancroid, which facilitates HIV transmission. In an experimental infection model in humans, papules develop within 24 h and either resolve or evolve into pustules. Pustules contain an abscess composed of PMNs and macrophages, while T cells, myeloid dendritic cells (DC) and macrophages form a loose granuloma below the abscess. In the failed pustular state, H. ducreyi is surrounded by phagocytes that do not ingest the organism. Although pustules form in some subjects, all infected sites resolve in other subjects. When pustule formers and resolvers are re-infected, they tend to segregate towards their initial outcome, confirming a host effect. PMNs and macrophages isolated from the blood of those who formed pustules twice (PP group) or resolved twice (RR group) did not differ in their ability to ingest H. ducreyi, suggesting that the environment at the site of infection modulates phagocytosis. In PP and RR subjects infected a third time, lesional transcripts differed between the groups, confriming that their local immune responses are different. Myeloid DC from both groups had a common transcript response to H. ducreyi, but each group had unique responses. Infected PP DC upregulated transcripts that were markers of DC maturation and markers of semi-mature or regulatory DC and downregulated transcripts known to promote DC maturation or antigen processing. Infected RR DC only upregulated transcripts of DC maturation. Our overall hypothesis is that the interaction of H. ducreyi with DC, and the interaction of infected DC with T cells are key determinants of effective (RR) or ineffective (PP) phagocytic responses in lesions. DC from the PP group likely promote a dysregulated Type 1 and Tr response that leads to an antiphagocytic cytokine environment, while DC from the RR group promote a Type 1 response that leads to a pro-phagocytic environment. To test these hypotheses, our specific aims include: comparison of transcripts in lesions collected 48 h after a third infection of the RR and PP groups; comparison of the gene expression and proteomic profiles of DC derived from the PP and the RR groups exposed to live H. ducreyi; testing whether DC pulsed with live H. ducreyi and co-cultured with T cells from the RR group result in Type 1 responses while co-cultures derived from the PP group lead to Type 1 and Tr responses; examination of whether the cytokines generated by H. ducreyi - DC - T cell interaction promotes or inhibits phagocytosis of the organism and of the mechanisms underlying the modulation of phagocytosis. We will confirm our in vitro results with observations made on biopsies obtained from PP and RR subjects who are re-infected. Lay summary: H. ducreyi is a germ that causes genital ulcers. When we infect human volunteers on the arm with the germ, some people develop disease while others clear the infection. We seek to answer an important question: Why do some people who become infected with a germ get sick, while others do not?

杜克雷嗜血杆菌会引起软下疳，从而促进艾滋病毒的传播。在实验性感染中 在人类模型中，丘疹在 24 小时内形成，然后消退或演变成脓疱。脓疱含有 由 PMN 和巨噬细胞组成的脓肿，而 T 细胞、骨髓树突状细胞 (DC) 和 巨噬细胞在脓肿下方形成松散的肉芽肿。在失败的脓疱状态下，H. ducreyi 是 被不吞噬生物体的吞噬细胞包围。尽管某些科目会形成脓疱，但所有科目 感染部位在其他受试者中消退。当脓疱形成者和消退者再次感染时，它们往往会 朝着最初的结果分离，确认宿主效应。从中分离出的中性粒细胞和巨噬细胞 两次形成脓疱（PP 组）或两次消退（RR 组）的患者的血液在其 摄入杜克雷螺杆菌的能力，表明感染部位的环境调节吞噬作用。 在第三次感染的 PP 和 RR 受试者中，各组之间的病变转录本不同，这证实了 他们的局部免疫反应是不同的。两组的髓样 DC 具有共同的转录反应 H. ducreyi，但每个组都有独特的反应。受感染的 PP DC 转录本上调 DC 成熟标记和半成熟或调节 DC 标记以及下调转录本 已知可促进 DC 成熟或抗原加工。感染的RR DC仅上调DC的转录本 成熟。我们的总体假设是 H. ducreyi 与 DC 的相互作用，以及 感染 T 细胞的 DC 是有效 (RR) 或无效 (PP) 吞噬反应的关键决定因素 病变。来自 PP 组的 DC 可能会促进 1 型和 Tr 反应失调，从而导致 抗吞噬细胞因子环境，而来自 RR 组的 DC 促进 1 型反应，导致 促吞噬细胞的环境。为了检验这些假设，我们的具体目标包括： RR组和PP组第三次感染后48小时收集的病灶转录本；基因比较 来自暴露于活杜克雷螺杆菌的 PP 和 RR 组的 DC 的表达和蛋白质组谱； 测试 DC 与活杜克雷嗜血杆菌脉冲并与来自 RR 组的 T 细胞共培养是否会导致 Type 1 反应，而来自 PP 组的共培养物导致 1 型和 Tr 反应；的检查 H. ducreyi - DC - T 细胞相互作用产生的细胞因子是否促进或抑制吞噬作用 吞噬作用调节的生物体和机制。我们将在体外确认 对从再次感染的 PP 和 RR 受试者获得的活检进行观察得到的结果。 概要：H. ducreyi 是一种引起生殖器溃疡的细菌。当我们感染人类志愿者时 手臂上带有细菌，有些人会患病，而另一些人则可以清除感染。我们试图回答一个 重要问题：为什么有些人感染细菌后会生病，而另一些人却不会？